Case report

INTRODUCTIONErdheim-Chester disease (ECD) is a non-Langerhans

form of histiocytosis that occurs in bone, the central nervous system, cardiovascular system, lungs, and kidneys, and it causes a variety of symptoms. The 5-year survival rate of patients with ECD is reportedly 68%.1 The presence of car-diovascular lesions and central nervous system lesions is a poor prognostic factor.2 There are reports that abnormalities of the central nervous system develop in half of ECD cases. Diabetes insipidus is also common in cases with panhypopi-tuitarism. In the literature, there are approximately 500 reports on ECD from around the world. ECD is more com-mon in men, and the average age of ECD patients is 55 years. Mutations of BRAF and NRAS, which are oncogenes in the mitogen-activated protein kinase pathway, have been found to be involved in the pathogenesis of ECD.3

The lesions contain foamy macrophages and multi-nucle-ated giant cells that are positive for CD68 and CD163, and negative for CD1a and S-100, and they are accompanied by fibrosis and lymphocyte infiltration. Although it is well-known that macrophages are broadly classified into M1-like and M2-like phenotypes,4 no study has yet characterized the

macrophages in ECD.Herein, we report an ECD case with typical histological

features, and we also examined the expression of M1/M2-related markers on the macrophages in the present case.

CASE REPORTA 68-year-old woman was referred to our hospital with a

suspected cranial pharyngeal tumor due to a history of grad-ual onset of binaural half blindness and cognitive decline. She denied any headaches, history of seizures, recent changes in weight, breast discharge, or changes in shoe size or facial features. She had no other significant medical or surgical history. Magnetic resonance imaging (MRI) with and with-out contrast of the brain revealed a multi-lobulated complex mass with both cystic and solid components in the suprasellar region measuring 19 mm × 19 mm × 18 mm (Figure 1A). The radiological differential diagnosis was craniopharyngi-oma, and endoscopic transnasal sphenoid sinus tumor removal was performed. The first postoperative pathological findings were not suggestive of a tumor. Therefore, we fol-lowed the follow-up policy for the remaining lesion. Symptoms, such as complaints of malaise, disorientation, and

A case of suprasellar Erdheim-Chester disease and characterization of macrophage phenotype

Keitaro Kai,1,2) Yoshihiro Komohara,2) Naoki Shinojima,1) Shigetoshi Yano,1) Yoshiki Mikami,3) Hideaki Yokoo,4) Akitake Mukasa1)

Erdheim-Chester disease (ECD) is a non-Langerhans form of histiocytosis that occurs in systemic organs, such as bone, the central nervous system, cardiovascular system, lungs, and kidneys. We report the case of a 68-year-old woman with a cranial pharyngeal tumor and a bone lesion in the tibia. The case was diagnosed as ECD. Pathological analysis showed the typical feature of foamy macrophage accumulation. The macrophages were positive for CD68, and negative for CD1a and S100. The BRAF V600E mutation was identified. In addition, immunohistochemistry was performed for the detailed characterization of the macrophages. The macrophages had low proliferative activity and an M2-like phenotype, and they expressed colony-stim-ulating factor-1 receptor (CSF1R) on the cell surface.

Keywords: Erdheim-Chester disease, macrophage, CSF1R

Received: July 22, 2020. Revised: August 26, 2020. Accepted: September 2, 2020. J-STAGE Advance Published: October 8, 2020 DOI:10.3960/jslrt.200321)Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan, 2)Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan, 3)Department of Diagnostic Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan, 4)Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, JapanCorresponding author: Yoshihiro Komohara, Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

E-mail: ycomo@kumamoto-u.ac.jpCopyright © 2020 The Japanese Society for Lymphoreticular Tissue Research

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

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hallucinations, appeared during the 2 years after surgery. MRI showed findings of tumor regrowth and ventricular enlargement at our facility. Hydrocephalus was also observed with the regrowth of the tumor (Figure 1B), and transcranial biopsy and ventriculoperitoneal shunt surgery were performed. After the operation, walking function and cognitive function improved to the same level as after the first operation. Pathological findings suggested ECD, and when a lower limb X-ray was taken, bone hardening was observed at the tibial end. Bone scintigraphy revealed simi-lar findings in the same site (Figure 1C). Although the pres-ent case was treated with the administration of steroid, the patient died suddenly 3 years after the first diagnosis. At the request of the family, no autopsy was performed, and the cause of death remains unknown.

The first postoperative pathological findings showed

granulation-like tissue with moderate inflammation, and a reactive lesion was suspected (Figure 2A). Histological examination of the second biopsy specimen revealed a xan-thogranulomatous lesion consisting of aggregations of foamy macrophages (Figure 2B). There was less connective tissue than at the first operation. Macrophages were multi-nuclear and varied in size. Large atypical or Touton-type giant cells were more prominent in the second biopsy specimen. Immunohistochemistry (IHC) showed that the macrophages were positive for CD68 and the BRAF V600E mutation (Figure 2C), but negative for CD1a and S-100 (data not shown). The BRAF V600E mutation was confirmed by DNA sequencing (Figure 2D). The present case was diag-nosed as ECD based on these observations.

We additionally performed IHC to examine macrophage proliferation and activation to characterize the macrophages

T1-WI GdT1-WI T2-WI

After four months After 10 months 2 years later

A

B

C

Fig. 1. Radiological findings. (A) Solid components in the suprasellar region were seen on MRI. (B) MRI images taken after the first surgery. (C) Bone scintigraphy after the second surgery.

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(Figure 2E). The Ki-67 labeling index was low in the histio-cytes; however, proliferating cell nuclear antigen (PCNA) was positive in 10% to 20% of the macrophages. The histio-cytes were also positive for CD11c, CD14, CD68, CD163, CD204, CD206, Iba-1, PU.1, and colony-stimulating factor-1 receptor (CSF1R), whereas the macrophages were negative for CD1a, CD169, and HLA-DR.

DISCUSSIONECD is a rare non-Langerhans form of histiocytosis that

is characterized by the tissue infiltration of macrophages and the subsequent fibrosis. In the present case, infiltrating mac-rophages were positive for PCNA, but negative for Ki67, indicating that the macrophages had low proliferative activ-ity. The origin of histiocytosis ECD remains unclear. Macrophages are classified into two subtypes according to their origin: from circulating monocytes (exudate macro-phages) or from the yolk sac/fetal liver (resident macro-phages).6 In the present case, the macrophage subtype remained unknown since there are no antibodies that can be used to distinguish monocyte-derived macrophages from

Fig. 2. Pathological examinations. Hematoxylin and eosin staining of lesions from the first operation (A) and the second operation (B). (C) IHC of CD68 and BRAF V600E. (D) Sequence showing a V600E mutation in the BRAF gene. (E) Additional IHCs were performed as described previously.5

Ki67 CD14

CD204 MCSF-R HLA-DR

CD163 CD169

CD206

Iba-1CD11c

PU.1PCNA

1st operation 2nd operationA

E

CD68 BRAF V600E

B

C D

50

100 100 20

μm

μm μm μm

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resident macrophages. Resident macrophages have higher proliferating or self-renewing activity than exudate macro-phages.7 However, we could not clarify the origin of macro-phages in ECD by this point. Foamy macrophages were strongly positive for M2-related markers, such as CD163, CD204, and CD206, whereas M1 markers, such as HLA-DR and CD169, were negative or weakly positive. This sug-gested that the foamy macrophages preferentially had a M2-like phenotype. IL-6, IL-12, interferon-α (IFN-α), and monocyte chemotactic protein-1 (MCP-1) levels were signifi-cantly higher in untreated ECD patients.8 Inflammatory cytokine/chemokine networks associated with senescence have also been suggested to be linked to the pathogenesis of ECD.9,10 Senescent cells induced macrophage polarization into M2-phenotype via the production of prostaglandin E2.11 IL-6 is known to induce M2-polarization.12 Transient stimu-lation with inflammatory molecules induced M1-polarization, however, we recently demonstrated that long-term stimula-tion with an inflammatory molecule induced M2-polarization in macrophages.13 Thus, we suggested the close association between cell senescence and M2-polarization in macrophages of ECD.

Although IFN-α can be a first-line therapy, no standard therapy for ECD has yet been established. In the present case, macrophages were strongly positive for CSF1R. Tenosynovial giant cell tumors are also macrophage-related tumors, and they also express CSF1R. It was recently reported that patients with Tenosynovial giant cell tumors who were treated with inhibitors of CSF1R showed a better clinical response than the untreated controls.14 In addition, a monoclonal antibody to CSF1R could deplete tumor-associ-ated macrophages in human solid tumors, although mono-therapy using these inhibitors or antibody was not significant for anti-cancer therapy.15 As such, anti-CSF1R therapy may also be beneficial as a treatment for ECD.

ACKNOWLEDGMENTWritten informed consent was obtained from patient, and

the additional study design was approved by the Kumamoto University Review Board (#2224).

CONFLICT OF INTERESTAll authors have no financial competing interests to

declare.

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